{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T05:42:15Z","timestamp":1790487735037,"version":"4.1.0"},"reference-count":129,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,3,12]],"date-time":"2021-03-12T00:00:00Z","timestamp":1615507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>\n                    The genetic alterations that cause the development of glucocorticoid and\/or mineralocorticoid producing benign adrenocortical tumors and hyperplasias have largely been elucidated over the past two decades through advances in genomics. In benign aldosterone-producing adrenocortical tumors and hyperplasias, alteration of intracellular calcium signaling has been found to be significant in aldosterone hypersecretion, with causative defects including those in\n                    <jats:italic>KCNJ5, ATP1A1, ATP2B3, CACNA1D, CACNA1H<\/jats:italic>\n                    , and\n                    <jats:italic>CLCN2.<\/jats:italic>\n                    In benign cortisol-producing adrenocortical tumors and hyperplasias abnormal cyclic adenosine monophosphate-protein kinase A signaling has been found to play a central role in tumorigenesis, with pathogenic variants in\n                    <jats:italic>GNAS, PRKAR1A, PRKACA, PRKACB, PDE11A<\/jats:italic>\n                    , and\n                    <jats:italic>PDE8B<\/jats:italic>\n                    being implicated. The role of this signaling pathway in the development of Cushing\u2019s syndrome and adrenocortical tumors was initially discovered through the study of the underlying genetic defects causing the rare multiple endocrine neoplasia syndromes McCune-Albright syndrome and Carney complex with subsequent identification of defects in genes affecting the cyclic adenosine monophosphate-protein kinase A pathway in sporadic tumors. Additionally, germline pathogenic variants in\n                    <jats:italic>ARMC5<\/jats:italic>\n                    , a putative tumor suppressor, were found to be a cause of cortisol-producing primary bilateral macronodular adrenal hyperplasia. This review describes the genetic causes of benign cortisol- and aldosterone-producing adrenocortical tumors.\n                  <\/jats:p>","DOI":"10.3389\/fendo.2021.632543","type":"journal-article","created":{"date-parts":[[2021,3,12]],"date-time":"2021-03-12T01:07:08Z","timestamp":1615511228000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":31,"title":["Molecular Genetic and Genomic Alterations in Cushing\u2019s Syndrome and Primary Aldosteronism"],"prefix":"10.3389","volume":"12","author":[{"given":"Crystal D. C.","family":"Kamilaris","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constantine A.","family":"Stratakis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fady","family":"Hannah-Shmouni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,3,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1310359","article-title":"Constitutive activation of PKA catalytic subunit in adrenal Cushing\u2019s syndrome","volume":"370","author":"Beuschlein","year":"2014","journal-title":"N Engl J Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0b013e31821ec4ce","article-title":"Primary bimorphic adrenocortical disease: cause of hypercortisolism in McCune-Albright syndrome","volume":"35","author":"Carney","year":"2011","journal-title":"Am J Surg Pathol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1038\/79238","article-title":"Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex","volume":"26","author":"Kirschner","year":"2000","journal-title":"Nat Genet"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199112123252403","article-title":"Activating mutations of the stimulatory G protein in the McCune-Albright syndrome","volume":"325","author":"Weinstein","year":"1991","journal-title":"N Engl J Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1304603","article-title":"ARMC5 mutations in macronodular adrenal hyperplasia with Cushing\u2019s syndrome","volume":"369","author":"Assie","year":"2013","journal-title":"N Engl J Med"},{"key":"B6","doi-asserted-by":"publisher","first-page":"894","DOI":"10.1016\/S2213-8587(20)30314-4","article-title":"Epidemiology of adrenal tumours in Olmsted County, Minnesota, USA: a population-based cohort study","volume":"8","author":"Ebbehoj","year":"2020","journal-title":"Lancet Diabetes Endocrinol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2015-4061","article-title":"The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline","volume":"101","author":"Funder","year":"2016","journal-title":"J Clin Endocrinol Metab"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2006.07.059","article-title":"A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients","volume":"48","author":"Rossi","year":"2006","journal-title":"J Am Coll Cardiol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2265.2007.02775.x","article-title":"Primary aldosteronism: renaissance of a syndrome","volume":"66","author":"Young","year":"2007","journal-title":"Clin Endocrinol (Oxf)"},{"key":"B10","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1152\/physrev.00030.2003","article-title":"Control of aldosterone secretion: a model for convergence in cellular signaling pathways","volume":"84","author":"Spat","year":"2004","journal-title":"Physiol Rev"},{"key":"B11","article-title":"Hypertension, increased aldosterone secretion and low plasma renin activity relieved by dexamethasone","volume":"95","author":"Sutherland","year":"1966","journal-title":"Can Med Assoc J"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/355262a0","article-title":"A chimaeric 11 beta-hydroxylase\/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension","volume":"355","author":"Lifton","year":"1992","journal-title":"Nature"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.85.9.6834","article-title":"Treatment of familial hyperaldosteronism type I: only partial suppression of adrenocorticotropin required to correct hypertension","volume":"85","author":"Stowasser","year":"2000","journal-title":"J Clin Endocrinol Metab"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.37.11.831","article-title":"A novel genetic locus for low renin hypertension: familial hyperaldosteronism type II maps to chromosome 7 (7p22)","volume":"37","author":"Lafferty","year":"2000","journal-title":"J Med Genet"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0053-8","article-title":"A gain-of-function mutation in the CLCN2 chloride channel gene causes primary aldosteronism","volume":"50","author":"Fernandes-Rosa","year":"2018","journal-title":"Nat Genet"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-018-0048-5","article-title":"CLCN2 chloride channel mutations in familial hyperaldosteronism type II","volume":"50","author":"Scholl","year":"2018","journal-title":"Nat Genet"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1126\/science.1198785","article-title":"K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension","volume":"331","author":"Choi","year":"2011","journal-title":"Sci (N Y NY)"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1093\/ajh\/hpz172","article-title":"Mosaicism for KCNJ5 Causing Early-Onset Primary Aldosteronism due to Bilateral Adrenocortical Hyperplasia","volume":"33","author":"Maria","year":"2020","journal-title":"Am J Hypertens"},{"key":"B19","doi-asserted-by":"publisher","first-page":"e06315","DOI":"10.7554\/eLife.06315","article-title":"Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism","volume":"4","author":"Scholl","year":"2015","journal-title":"Elife"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2695","article-title":"Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism","volume":"45","author":"Scholl","year":"2013","journal-title":"Nat Genet"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1530\/ERC-20-0384","article-title":"Phosphodiesterase 2A and 3B variants are associated with primary aldosteronism","volume":"28","author":"Rassi-Cruz","year":"2021","journal-title":"Endocr Relat Cancer"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2014-4167","article-title":"Primary Aldosteronism and ARMC5 Variants","volume":"100","author":"Zilbermint","year":"2015","journal-title":"J Clin Endocrinol Metab"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/jhh.2015.98","article-title":"ARMC5 mutation analysis in patients with primary aldosteronism and bilateral adrenal lesions","volume":"30","author":"Mulatero","year":"2016","journal-title":"J Hum Hypertens"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2716","article-title":"Somatic mutations in ATP1A1 and CACNA1D underlie a common subtype of adrenal hypertension","volume":"45","author":"Azizan","year":"2013","journal-title":"Nat Genet"},{"key":"B25","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1038\/ng.2550","article-title":"Somatic mutations in ATP1A1 and ATP2B3 lead to aldosterone-producing adenomas and secondary hypertension","volume":"45","author":"Beuschlein","year":"2013","journal-title":"Nat Genet"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.114.03419","article-title":"Genetic spectrum and clinical correlates of somatic mutations in aldosterone-producing adenoma","volume":"64","author":"Fernandes-Rosa","year":"2014","journal-title":"Hypertension"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0041926","article-title":"Comprehensive Re-Sequencing of Adrenal Aldosterone Producing Lesions Reveal Three Somatic Mutations near the KCNJ5 Potassium Channel Selectivity Filter","volume":"7","author":"Akerstrom","year":"2012","journal-title":"PloS One"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.111.186478","article-title":"Prevalence, clinical, and molecular correlates of KCNJ5 mutations in primary aldosteronism","volume":"59","author":"Boulkroun","year":"2012","journal-title":"Hypertension"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0147590","article-title":"Genetics of Aldosterone-Producing Adenoma in Korean Patients","volume":"11","author":"Hong","year":"2016","journal-title":"PloS One"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2015-2149","article-title":"A Meta-Analysis of Somatic KCNJ5 K+ Channel Mutations In 1636 Patients With an Aldosterone-Producing Adenoma","volume":"100","author":"Lenzini","year":"2015","journal-title":"J Clin Endocr Metab"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/srep11396","article-title":"Prevalence and clinical correlates of somatic mutation in aldosterone producing adenoma-Taiwanese population","volume":"5","author":"Wu","year":"2015","journal-title":"Sci Rep-Uk"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s12276-019-0337-9","article-title":"Genetic causes of primary aldosteronism","volume":"51","author":"Seidel","year":"2019","journal-title":"Exp Mol Med"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.118.12070","article-title":"Genetic Characteristics of Aldosterone-Producing Adenomas in Blacks","volume":"73","author":"Nanba","year":"2019","journal-title":"Hypertension"},{"key":"B34","doi-asserted-by":"publisher","first-page":"19546","DOI":"10.1038\/srep19546","article-title":"Activating mutations in CTNNB1 in aldosterone producing adenomas","volume":"6","author":"Akerstrom","year":"2016","journal-title":"Sci Rep"},{"key":"B35","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1093\/hmg\/ddt484","article-title":"WNT\/beta-catenin signalling is activated in aldosterone-producing adenomas and controls aldosterone production","volume":"23","author":"Berthon","year":"2014","journal-title":"Hum Mol Genet"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1111\/cen.12873","article-title":"Novel somatic mutations in primary hyperaldosteronism are related to the clinical, radiological and pathological phenotype","volume":"83","author":"Scholl","year":"2015","journal-title":"Clin Endocrinol (Oxf)"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2265.2007.03033.x","article-title":"Frequent mutations of beta-catenin gene in sporadic secreting adrenocortical adenomas","volume":"68","author":"Tadjine","year":"2008","journal-title":"Clin Endocrinol (Oxf)"},{"key":"B38","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.devcel.2009.06.016","article-title":"Wnt\/beta-Catenin Signaling: Components, Mechanisms, and Diseases","volume":"17","author":"MacDonald","year":"2009","journal-title":"Dev Cell"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1504869","article-title":"Pregnancy, Primary Aldosteronism, and Adrenal CTNNB1 Mutations","volume":"373","author":"Teo","year":"2015","journal-title":"N Engl J Med"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2018-00087","article-title":"Genetic Characterization of GnRH\/LH-Responsive Primary Aldosteronism","volume":"103","author":"Gagnon","year":"2018","journal-title":"J Clin Endocrinol Metab"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.119.14349","article-title":"Somatic CACNA1H Mutation As a Cause of Aldosterone-Producing Adenoma","volume":"75","author":"Nanba","year":"2020","journal-title":"Hypertension"},{"key":"B42","doi-asserted-by":"publisher","first-page":"bvaa123","DOI":"10.1210\/jendso\/bvaa123","article-title":"Identification of Somatic Mutations in CLCN2 in Aldosterone-Producing Adenomas","volume":"4","author":"Rege","year":"2020","journal-title":"J Endocr Soc"},{"key":"B43","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1210\/clinem\/dgaa484","article-title":"International histopathology consensus for unilateral primary aldosteronism","volume":"106","author":"Williams","year":"2021","journal-title":"J Clin Endocrinol Metab"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(14)61375-1","article-title":"Cushing\u2019s syndrome","volume":"386","author":"Lacroix","year":"2015","journal-title":"Lancet"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2265.1994.tb02486.x","article-title":"Morbidity and mortality in Cushing\u2019s disease: an epidemiological approach","volume":"40","author":"Etxabe","year":"1994","journal-title":"Clin Endocrinol (Oxf)"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.86.1.7093","article-title":"Kristensen L et al: Incidence and late prognosis of cushing\u2019s syndrome: a population-based study","volume":"86","author":"Lindholm","year":"2001","journal-title":"J Clin Endocrinol Metab"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1055\/a-1107-2972","article-title":"A Gene-Based Classification of Primary Adrenocortical Hyperplasias","volume":"52","author":"Hannah-Shmouni","year":"2020","journal-title":"Horm Metab Res"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1038\/ncpendmet0648","article-title":"Genetics of adrenal tumors associated with Cushing\u2019s syndrome: a new classification for bilateral adrenocortical hyperplasias","volume":"3","author":"Stratakis","year":"2007","journal-title":"Nat Clin Pract Endocrinol Metab"},{"key":"B49","article-title":"Fibrous Dysplasia\/McCune-Albright Syndrome","volume-title":"GeneReview\u00ae [Internet]","author":"Boyce","year":"1993"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3432","article-title":"Assembly of allosteric macromolecular switches: lessons from PKA","volume":"13","author":"Taylor","year":"2012","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/j.lpm.2018.07.005","article-title":"Genetics of micronodular adrenal hyperplasia and Carney complex","volume":"47","author":"Tirosh","year":"2018","journal-title":"Presse Med"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2008-2333","article-title":"Mutations in regulatory subunit type 1A of cyclic adenosine 5\u2019-monophosphate-dependent protein kinase (PRKAR1A): phenotype analysis in 353 patients and 80 different genotypes","volume":"94","author":"Bertherat","year":"2009","journal-title":"J Clin Endocrinol Metab"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1097\/00005792-198507000-00007","article-title":"The complex of myxomas, spotty pigmentation, and endocrine overactivity","volume":"64","author":"Carney","year":"1985","journal-title":"Med (Baltimore)"},{"key":"B54","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1159\/000345669","article-title":"Carney Complex","volume":"41","author":"Espiard","year":"2013","journal-title":"Front Horm Res"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1055\/a-0753-4943","article-title":"Carneya Complex","volume":"127","author":"Kamilaris","year":"2019","journal-title":"Exp Clin Endocrinol Diabetes"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.86.9.7903","article-title":"Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation","volume":"86","author":"Stratakis","year":"2001","journal-title":"J Clin Endocrinol Metab"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1007\/s11102-006-0266-1","article-title":"PRKAR1A mutations in primary pigmented nodular adrenocortical disease","volume":"9","author":"Cazabat","year":"2006","journal-title":"Pituitary"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.30279","article-title":"Eyelid myxoma in Carney complex without PRKAR1A allelic loss","author":"Tsilou","year":"2004","journal-title":"Am J Med Genet A"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddg160","article-title":"Protein kinase-A activity in PRKAR1A-mutant cells, and regulation of mitogen-activated protein kinases ERK1\/2","volume":"12","author":"Robinson-White","year":"2003","journal-title":"Hum Mol Genet"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-17-0361","article-title":"Genetics of tumors of the adrenal cortex","volume":"25","author":"Bonnet-Serrano","year":"2018","journal-title":"Endocr Relat Cancer"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.40.4.268","article-title":"Chromosome 2 (2p16) abnormalities in Carney complex tumours","volume":"40","author":"Matyakhina","year":"2003","journal-title":"J Med Genet"},{"key":"B62","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1172\/JCI118467","article-title":"Carney complex, a familial multiple neoplasia and lentiginosis syndrome. Analysis of 11 kindreds and linkage to the short arm of chromosome 2","volume":"97","author":"Stratakis","year":"1996","journal-title":"J Clin Invest"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc1309730","article-title":"PRKACB and Carney complex","volume":"370","author":"Forlino","year":"2014","journal-title":"N Engl J Med"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-20-0309","article-title":"PRKACB variants in skeletal disease or adrenocortical hyperplasia: effects on protein kinase A","volume":"27","author":"Espiard","year":"2020","journal-title":"Endocr Relat Cancer"},{"key":"B65","article-title":"Molecular and functional analysis of PRKAR1A and its locus (17q22-24) in sporadic adrenocortical tumors: 17q losses, somatic mutations, and protein kinase A expression and activity","volume":"63","author":"Bertherat","year":"2003","journal-title":"Cancer Res"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2011-3327","article-title":"Adrenocortical cancer in Carney complex: a paradigm of endocrine tumor progression or an association of genetic predisposing factors","volume":"97","author":"Bertherat","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1210\/js.2017-00231","article-title":"Corticotropinoma as a Component of Carney Complex","volume":"1","author":"Hernandez-Ramirez","year":"2017","journal-title":"J Endocr Soc"},{"key":"B68","doi-asserted-by":"publisher","first-page":"K7","DOI":"10.1530\/EJE-17-0227","article-title":"PRKAR1A mutation causing pituitary-dependent Cushing disease in a patient with Carney complex","volume":"177","author":"Kiefer","year":"2017","journal-title":"Eur J Endocrinol"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-020-01018-4","article-title":"Genomic and sequence variants of protein kinase A regulatory subunit type 1beta (PRKAR1B) in patients with adrenocortical disease and Cushing syndrome","volume":"23","author":"Drougat","year":"2021","journal-title":"Genet Med"},{"key":"B70","doi-asserted-by":"publisher","first-page":"794","DOI":"10.1038\/ng1809","article-title":"A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 (PDE11A) in individuals with adrenocortical hyperplasia","volume":"38","author":"Horvath","year":"2006","journal-title":"Nat Genet"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2010-1704","article-title":"Frequent phosphodiesterase 11A gene (PDE11A) defects in patients with Carney complex (CNC) caused by PRKAR1A mutations: PDE11A may contribute to adrenal and testicular tumors in CNC as a modifier of the phenotype","volume":"96","author":"Libe","year":"2011","journal-title":"J Clin Endocrinol Metab"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-08-0106","article-title":"Phosphodiesterase 11A (PDE11A) and genetic predisposition to adrenocortical tumors","volume":"14","author":"Libe","year":"2008","journal-title":"Clin Cancer Res"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2010-1655","article-title":"Phosphodiesterase 11A (PDE11A) genetic variants may increase susceptibility to prostatic cancer","volume":"96","author":"Faucz","year":"2011","journal-title":"J Clin Endocrinol Metab"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-15-0034","article-title":"Rare inactivating PDE11A variants associated with testicular germ cell tumors","volume":"22","author":"Pathak","year":"2015","journal-title":"Endocr Relat Cancer"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc0706182","article-title":"Mutation in PDE8B, a cyclic AMP-specific phosphodiesterase in adrenal hyperplasia","volume":"358","author":"Horvath","year":"2008","journal-title":"N Engl J Med"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2265.2012.04366.x","article-title":"Identification of novel genetic variants in phosphodiesterase 8B (PDE8B), a cAMP-specific phosphodiesterase highly expressed in the adrenal cortex, in a cohort of patients with adrenal tumours","volume":"77","author":"Rothenbuhler","year":"2012","journal-title":"Clin Endocrinol (Oxf)"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-14-1154","article-title":"Germline PRKACA amplification causes variable phenotypes that may depend on the extent of the genomic defect: molecular mechanisms and clinical presentations","volume":"172","author":"Lodish","year":"2015","journal-title":"Eur J Endocrinol"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2265.2008.03273.x","article-title":"Detection of somatic beta-catenin mutations in primary pigmented nodular adrenocortical disease (PPNAD)","volume":"69","author":"Tadjine","year":"2008","journal-title":"Clin Endocrinol (Oxf)"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2008-0631","article-title":"Wnt\/beta-catenin and 3\u2019,5\u2019-cyclic adenosine 5\u2019-monophosphate\/protein kinase A signaling pathways alterations and somatic beta-catenin gene mutations in the progression of adrenocortical tumors","volume":"93","author":"Gaujoux","year":"2008","journal-title":"J Clin Endocrinol Metab"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1215245","article-title":"Intraadrenal corticotropin in bilateral macronodular adrenal hyperplasia","volume":"369","author":"Louiset","year":"2013","journal-title":"N Engl J Med"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2009-0516","article-title":"Clinical and genetic heterogeneity, overlap with other tumor syndromes, and atypical glucocorticoid hormone secretion in adrenocorticotropin-independent macronodular adrenal hyperplasia compared with other adrenocortical tumors","volume":"94","author":"Hsiao","year":"2009","journal-title":"J Clin Endocrinol Metab"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2265.2008.03471.x","article-title":"Familial vasopressin-sensitive ACTH-independent macronodular adrenal hyperplasia (VPs-AIMAH): clinical studies of three kindreds","volume":"70","author":"Gagliardi","year":"2009","journal-title":"Clin Endocrinol"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1172-8-142","article-title":"ACTH-independent macronodular adrenocortical hyperplasia reveals prevalent aberrant in vivo and in vitro responses to hormonal stimuli and coupling of arginine-vasopressin type 1a receptor to 11 beta-hydroxylase","volume":"8","author":"Hofland","year":"2013","journal-title":"Orphanet J Rare Dis"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1007\/s00063-002-1220-2","article-title":"Catecholamine-dependent hereditary Cushing\u2019s syndrome - Follow-up after unilateral adrenalectomy","volume":"97","author":"Imohl","year":"2002","journal-title":"Med Klin"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199210013271402","article-title":"Gastric inhibitory polypeptide-dependent cortisol hypersecretion\u2013a new cause of Cushing\u2019s syndrome","volume":"327","author":"Lacroix","year":"1992","journal-title":"N Engl J Med"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199911183412104","article-title":"Leuprolide acetate therapy in luteinizing hormone\u2013dependent Cushing\u2019s syndrome","volume":"341","author":"Lacroix","year":"1999","journal-title":"N Engl J Med"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2265.2005.02387.x","article-title":"Ectopic expression of vasopressin V1b and V2 receptors in the adrenal glands of familial ACTH-independent macronodular adrenal hyperplasia","volume":"63","author":"Lee","year":"2005","journal-title":"Clin Endocrinol"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-10-0195","article-title":"Aberrant cortisol regulations in bilateral macronodular adrenal hyperplasia: a frequent finding in a prospective study of 32 patients with overt or subclinical Cushing\u2019s syndrome","volume":"163","author":"Libe","year":"2010","journal-title":"Eur J Endocrinol"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.1210\/jc.85.10.3531","article-title":"Are ectopic or abnormal membrane hormone receptors frequently present in adrenal Cushing\u2019s syndrome","volume":"85","author":"Mircescu","year":"2000","journal-title":"J Clin Endocrinol Metab"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1385\/ENDO:19:3:319","article-title":"Inherited adrenocorticotropin-independent macronodular adrenal hyperplasia with abnormal cortisol secretion by vasopressin and catecholamines - Detection of the aberrant hormone receptors on adrenal gland","volume":"19","author":"Miyamura","year":"2002","journal-title":"Endocrine"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199210013271403","article-title":"Food-dependent Cushing\u2019s syndrome mediated by aberrant adrenal sensitivity to gastric inhibitory polypeptide","volume":"327","author":"Reznik","year":"1992","journal-title":"N Engl J Med"},{"key":"B92","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1530\/eje.1.02324","article-title":"Familial adrenocorticotropin-independent macronodular adrenal hyperplasia with aberrant serotonin and vasopressin adrenal receptors","volume":"156","author":"Vezzosi","year":"2007","journal-title":"Eur J Endocrinol"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.92184","article-title":"Adrenal GIPR expression and chromosome 19q13 microduplications in GIP-dependent Cushing\u2019s syndrome","volume":"2","author":"Lecoq","year":"2017","journal-title":"JCI Insight"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2014-4204","article-title":"ARMC5 Mutations in a Large Cohort of Primary Macronodular Adrenal Hyperplasia: Clinical and Functional Consequences","volume":"100","author":"Espiard","year":"2015","journal-title":"J Clin Endocrinol Metab"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2013-4280","article-title":"Macronodular adrenal hyperplasia due to mutations in an armadillo repeat containing 5 (ARMC5) gene: a clinical and genetic investigation","volume":"99","author":"Faucz","year":"2014","journal-title":"J Clin Endocrinol Metab"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2014-1265","article-title":"ARMC5 mutations are common in familial bilateral macronodular adrenal hyperplasia","volume":"99","author":"Gagliardi","year":"2014","journal-title":"J Clin Endocrinol Metab"},{"key":"B97","doi-asserted-by":"publisher","first-page":"13834","DOI":"10.1038\/ncomms13834","article-title":"Armc5 deletion causes developmental defects and compromises T-cell immune responses","volume":"8","author":"Hu","year":"2017","journal-title":"Nat Commun"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-0593","article-title":"Mutations of beta-catenin in adrenocortical tumors: activation of the Wnt signaling pathway is a frequent event in both benign and malignant adrenocortical tumors","volume":"65","author":"Tissier","year":"2005","journal-title":"Cancer Res"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddx235","article-title":"Age-dependent effects of Armc5 haploinsufficiency on adrenocortical function","volume":"26","author":"Berthon","year":"2017","journal-title":"Hum Mol Genet"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-20-0273","article-title":"ARMC5 variants in PRKAR1A-mutated patients modify cortisol levels and Cushing\u2019s syndrome","volume":"27","author":"Maria","year":"2020","journal-title":"Endocr Relat Cancer"},{"key":"B101","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2014-2648","article-title":"Molecular and clinical evidence for an ARMC5 tumor syndrome: concurrent inactivating germline and somatic mutations are associated with both primary macronodular adrenal hyperplasia and meningioma","volume":"100","author":"Elbelt","year":"2015","journal-title":"J Clin Endocrinol Metab"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-11-0679","article-title":"Adrenal involvement in MEN1. Analysis of 715 cases from the Groupe d\u2019etude des Tumeurs Endocrines database","volume":"166","author":"Gatta-Cherifi","year":"2012","journal-title":"Eur J Endocrinol"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-10-1497","article-title":"Inactivation of the APC gene is constant in adrenocortical tumors from patients with familial adenomatous polyposis but not frequent in sporadic adrenocortical cancers","volume":"16","author":"Gaujoux","year":"2010","journal-title":"Clin Cancer Res"},{"key":"B104","doi-asserted-by":"publisher","DOI":"10.1016\/j.juro.2012.07.139","article-title":"Adrenal nodular hyperplasia in hereditary leiomyomatosis and renal cell cancer","volume":"189","author":"Shuch","year":"2013","journal-title":"J Urol"},{"key":"B105","doi-asserted-by":"publisher","DOI":"10.1097\/DCR.0000000000001008","article-title":"Characteristics of Adrenal Masses in Familial Adenomatous Polyposis","volume":"61","author":"Shiroky","year":"2018","journal-title":"Dis Colon Rectum"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.1126\/science.276.5311.404","article-title":"Positional cloning of the gene for multiple endocrine neoplasia-type 1","volume":"276","author":"Chandrasekharappa","year":"5311","journal-title":"Sci (N Y NY) 1997"},{"key":"B107","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/6.7.1177","article-title":"Identification of the multiple endocrine neoplasia type 1 (MEN1) gene","volume":"6","author":"Lemmens","year":"1997","journal-title":"Hum Mol Genet"},{"key":"B108","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1002\/humu.20605","article-title":"Multiple endocrine neoplaslia type 1 (MEN 1): Analysis of 1336 mutations reported in the first decade following identification of the gene","volume":"29","author":"Lemos","year":"2008","journal-title":"Hum Mutat"},{"key":"B109","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1016\/j.tibs.2013.05.005","article-title":"Menin: a scaffold protein that controls gene expression and cell signaling","volume":"38","author":"Matkar","year":"2013","journal-title":"Trends Biochem Sci"},{"key":"B110","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2019.00339","article-title":"Multiple Endocrine Neoplasia Type 1 (MEN1): An Update and the Significance of Early Genetic and Clinical Diagnosis","volume":"10","author":"Kamilaris","year":"2019","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B111","doi-asserted-by":"publisher","DOI":"10.1086\/320124","article-title":"Localization of a gene (MCUL1) for multiple cutaneous leiomyomata and uterine fibroids to chromosome 1q42.3-q43","volume":"68","author":"Alam","year":"2001","journal-title":"Am J Hum Genet"},{"key":"B112","doi-asserted-by":"publisher","DOI":"10.1002\/path.1686","article-title":"Evidence of increased microvessel density and activation of the hypoxia pathway in tumours from the hereditary leiomyomatosis and renal cell cancer syndrome","volume":"205","author":"Pollard","year":"2005","journal-title":"J Pathol"},{"key":"B113","doi-asserted-by":"publisher","DOI":"10.1038\/ncpuro0711","article-title":"Mechanisms of disease: hereditary leiomyomatosis and renal cell cancer\u2013a distinct form of hereditary kidney cancer","volume":"4","author":"Sudarshan","year":"2007","journal-title":"Nat Clin Pract Urol"},{"key":"B114","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2004-2377","article-title":"Hereditary leiomyomatosis associated with bilateral, massive, macronodular adrenocortical disease and atypical cushing syndrome: a clinical and molecular genetic investigation","volume":"90","author":"Matyakhina","year":"2005","journal-title":"J Clin Endocrinol Metab"},{"key":"B115","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddt639","article-title":"Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas","volume":"23","author":"Castro-Vega","year":"2014","journal-title":"Hum Mol Genet"},{"key":"B116","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2014-1659","article-title":"Germline FH mutations presenting with pheochromocytoma","volume":"99","author":"Clark","year":"2014","journal-title":"J Clin Endocrinol Metab"},{"key":"B117","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2012-2275","article-title":"Phosphodiesterase 11A (PDE11A) gene defects in patients with acth-independent macronodular adrenal hyperplasia (AIMAH): functional variants may contribute to genetic susceptibility of bilateral adrenal tumors","volume":"97","author":"Vezzosi","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"key":"B118","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2009-2321","article-title":"Cushing syndrome in the McCune-Albright syndrome","volume":"95","author":"Brown","year":"2010","journal-title":"J Clin Endocrinol Metab"},{"key":"B119","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2005-2608","article-title":"17q22-24 chromosomal losses and alterations of protein kinase a subunit expression and activity in adrenocorticotropin-independent macronodular adrenal hyperplasia","volume":"91","author":"Bourdeau","year":"2006","journal-title":"J Clin Endocrinol Metab"},{"key":"B120","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2003.10.052","article-title":"Constitutive activation of the human ACTH receptor resulting from a synergistic interaction between two naturally occurring missense mutations in the MC2R gene","volume":"213","author":"Swords","year":"2004","journal-title":"Mol Cell Endocrinol"},{"key":"B121","doi-asserted-by":"publisher","DOI":"10.1007\/s10689-013-9642-y","article-title":"Whole exome sequencing identifies mutation of EDNRA involved in ACTH-independent macronodular adrenal hyperplasia","volume":"12","author":"Zhu","year":"2013","journal-title":"Fam Cancer"},{"key":"B122","doi-asserted-by":"publisher","DOI":"10.1002\/path.5014","article-title":"Cyclic AMP-dependent protein kinase catalytic subunit A (PRKACA): the expected, the unexpected, and what might be next","volume":"244","author":"Stratakis","year":"2018","journal-title":"J Pathol"},{"key":"B123","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2016.24","article-title":"A genetic and molecular update on adrenocortical causes of Cushing syndrome","volume":"12","author":"Lodish","year":"2016","journal-title":"Nat Rev Endocrinol"},{"key":"B124","doi-asserted-by":"publisher","DOI":"10.1210\/en.2018-00775","article-title":"Alterations in Protein Kinase A Substrate Specificity as a Potential Cause of Cushing Syndrome","volume":"160","author":"Bathon","year":"2019","journal-title":"Endocrinology"},{"key":"B125","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.98296","article-title":"Activating PRKACB somatic mutation in cortisol-producing adenomas","volume":"3","author":"Espiard","year":"2018","journal-title":"JCI Insight"},{"key":"B126","doi-asserted-by":"publisher","DOI":"10.1126\/science.1249484","article-title":"Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma","volume":"343","author":"Honeyman","year":"6174","journal-title":"Sci (N Y NY) 2014"},{"key":"B127","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1053\/j.gastro.2019.10.028","article-title":"Recurrent Rearrangements in PRKACA and PRKACB in Intraductal Oncocytic Papillary Neoplasms of the Pancreas and Bile Duct","volume":"158","author":"Singhi","year":"2020","journal-title":"Gastroenterology"},{"key":"B128","doi-asserted-by":"publisher","DOI":"10.1002\/path.4899","article-title":"Microinsertions in PRKACA cause activation of the protein kinase A pathway in cardiac myxoma","volume":"242","author":"Tseng","year":"2017","journal-title":"J Pathol"},{"key":"B129","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-09-0027","article-title":"Abnormalities of cAMP signaling are present in adrenocortical lesions associated with ACTH-independent Cushing syndrome despite the absence of mutations in known genes","volume":"161","author":"Bimpaki","year":"2009","journal-title":"Eur J Endocrinol"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2021.632543\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,12]],"date-time":"2021-03-12T01:07:12Z","timestamp":1615511232000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2021.632543\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,12]]},"references-count":129,"alternative-id":["10.3389\/fendo.2021.632543"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2021.632543","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,12]]},"article-number":"632543"}}